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Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) continues to be the gold-standard treatment for Parkinson's disease (PD). Despite clear symptomatic benefit, long-term L-DOPA use often results in the development of L-DOPA-induced dyskinesia (LID), significantly reducing quality of life and increasing costs for PD patients and their caregivers. Accumulated research has demonstrated that several pre- and post-synaptic mechanisms contribute to LID development and expression. In particular, raphe-striatal hyperinnervation and unregulated DA release from 5-HT terminals is postulated to play a central role in LID manifestation. As such, manipulation of the 5-HT system has garnered considerable attention. Both pre-clinical and clinical research has supported the potential of modulating the 5-HT system for LID prevention and treatment. This review discusses the rationale for continued investigation of several potential anti-dyskinetic strategies including 5-HT stimulation of 5-HT1A and 5-HT1B receptors and blockade of 5-HT2A receptors and SERT. We present the latest findings from experimental and clinical investigations evaluating these 5-HT targets with the goal of identifying those with translational promise and the challenges associated with each.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.

Background: The serotonergic system is a well‐established modulator of l‐dopa‐induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5‐HT1A) reduces l‐dopa‐induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin‐mediated approaches. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5‐HT1A agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l‐dopa‐induced dyskinesia without compromising l‐dopa‐mediated motor improvements. Objectives: The goal of the present study was to characterize Vilazodone's effects on l‐dopa‐induced behaviors, neurochemistry and gene expression in unilateral 6‐hydroxydopamine‐lesioned hemi‐parkinsonian rats. Methods: In experiments 1 and 2, l‐dopa‐naïve and l‐dopa‐primed animals were coadministered Vilazodone and l‐dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5‐HT1A or serotonin receptor subtype 1B blockade prior to Vilazodone–l‐dopa coadministration. Results: Vilazodone significantly suppressed developing and established l‐dopa‐induced dyskinesia without compromising the promotor effects of l‐dopa therapy. In the dopamine‐depleted striatum, Vilazodone–l‐dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l‐dopa‐induced c‐Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D1 receptor‐mediated direct pathway overactivity. Only 5‐HT1A antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter‐dependent effects and 5‐HT1A receptors in Vilazodone's actions. Conclusions: Our findings show Vilazodone has a serotonin‐dependent effect on rodent l‐dopa‐induced dyskinesia and implicate the potential for repositioning Vilazodone against l‐dopa‐induced dyskinesia development and expression in Parkinson's disease patients. © 2018 International Parkinson and Movement Disorder Society

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